Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models
- Author:
Seong Hee KANG
1
;
Hyung Joon YIM
;
Ji-won HWANG
;
Mi-jung KIM
;
Young-Sun LEE
;
Young Kul JUNG
;
Hyungshin YIM
;
Baek-Hui KIM
;
Hae-Chul PARK
;
Yeon Seok SEO
;
Ji Hoon KIM
;
Jong Eun YEON
;
Soon Ho UM
;
Kwan Soo BYUN
Author Information
- Publication Type:2
- From:The Korean Journal of Internal Medicine 2022;37(4):745-756
- CountryRepublic of Korea
- Language:English
-
Abstract:
Background/Aims:Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects.
Methods:The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis.
Results:The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl-2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2.
Conclusions:The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis.
